The hepatitis G virus (HGV) is a newly discovered member of the Flaviviridae family that has approximately 25% homology with hepatitis C virus. Its clinical significance is unknown. We have studied HGV and its relation to blood transfusion risk. HGV was found in approximately 1.5% of the donor population and was shown to be transfusion-transmitted by demonstrating the acute appearance of HGV RNA following transfusion, by demonstrating linkage between HGV-positive donors and infected recipients, and by showing a higher incidence in transfused subjects than in non- transfused controls. HGV was shown to persist in the majority of infected subjects, but near 85% appear to clear the virus over time. Although 3 of 13 patients (23%) with non-A, non-B, non-C transfusion-associated hepatitis had acute HGV infection, the causal role of HGV in these cases is not clear because there was no definite temporal relationship between HGV RNA level and alanine transaminase (ALT) elevations, and because one case had alternative explanations for the ALT abnormalities. Overall, of 35 observed and 84 projected HGV infections, only 4% occurred in patients with hepatitis (the 3 cases described above), 7% occurred in those with coexisting hepatitis C where the ALT elevations were shown to be HCV related, 16% were in recipients who had such minor ALT elevations that they were not classified as having hepatitis, and 73% occurred in recipients with no biochemical or clinical evidence of hepatitis. Hence, the vast majority of HCV-infected patients have no evidence of liver disease, and in the few that do, causality cannot be proved. Similarly, we have studied HGV in renal dialysis patients, hemophiliacs, intravenous drug users, and patients with acute and chronic non-A, B, C, D, E hepatitis. Although the prevalence of HGV is very high among parenterally exposed individuals (10% to 20%), there is no association with liver disease in these HGV-infected populations. Among HGV and HCV co-infected patients, it was shown that HGV did not worsen the course of coexistent hepatitis C.